Cocaine High Caused By Interference In Neuronal Receiving Stations

Date:

December 7, 2006

Source:

Cell Press

Summary:

Researchers have found evidence for a fundamental molecular mechanism underlying the hyperactive high of cocaine. In studies with rats, they have traced the effect to interactions between two types of receiving stations in neurons for nerve signals from their neighbors. The researchers' studies in rats found that when the animals received cocaine, a component of a receptor for the neurotransmitter dopamine tends to grab onto a component of a receptor for glutamate. The result, they found, was interference with normal activation of this glutamate receptor.

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Researchers have found evidence for a fundamental molecular mechanism underlying the hyperactive high of cocaine. In studies with rats, they have traced the effect to interactions between two types of receiving stations in neurons for nerve signals from their neighbors. The researchers' studies in rats found that when the animals received cocaine, a component of a receptor for the neurotransmitter dopamine tends to grab onto a component of a receptor for glutamate. The result, they found, was interference with normal activation of this glutamate receptor.

John Wang, of the University of Missouri, Kansas City School of Medicine, and his colleagues published their findings in the December 7, 2006, issue of the journal Neuron, published by Cell Press.

Neurons trigger nerve impulses in their neighbors by launching bursts of chemicals called neurotransmitters at them. The neurotransmitters activate protein receptors on the receiving neurons, which induce the nerve impulses in the receiving cell. These receptors also adjust themselves in complex ways to alter the sensitivity of the receiving neuron to stimulation.

Researchers had long known that cocaine affects both dopamine and glutamate receptors on neurons, but the molecular details of those effects were unknown. In their experiments, Wang and colleagues first determined that cocaine reduces the activation of glutamate-responsive neurons by affecting a specific component, or subunit, of the receptor, called NR2B.

Further experiments revealed that when rats were given cocaine, a specific subunit of dopamine receptors, called D2R, tended to attach to the NR2B subunit and was responsible for preventing the normal activation of the glutamate receptor. Such activation normally involves addition to NR2B of a molecular group called a phosphate by an enzyme called a kinase, and the cocaine-induced D2R attachment blocked this event.

Wang and his colleagues found that this interaction between D2R and NR2B occurred specifically in the striatum of the brain--the region known to be responsible for cocaine's stimulating effects.

The researchers also analyzed whether this interaction between D2R and NR2B affected the rats' behavioral response to cocaine--specifically the hyperactivity and intensive sniffing and biting the drug elicits in the animals. They found that drugs that either activated the D2R subunit or inactivated the NR2B subunit tended to enhance such behavioral responses to cocaine.

"These results provide strong evidence supporting a critical role of the D2R-NR2B interaction in mediating cocaine's effect on [kinase binding and phosphorylation] and in constructing a full-scale motor response to cocaine," concluded the researchers.

The researchers include Xianyu Liu, Limin Mao, Guochi Zhang, Nikhil K. Parelkar, Eugene E. Fibuch, Michelle Haines, and John Q. Wang of University of Missouri, Kansas City School of Medicine in Kansas City, MO; Xiangping Chu, Minghua Li, and Zhigang Xiong of Robert S. Dow Neurobiology Laboratories, Legacy Research in Portland, OR; Min Wang and Fang Liu of University of Toronto in Toronto, Canada; Hongxiang Lan and Kim A. Neve Oregon Health and Science University and Veterans Affairs Medical Center in Portland, OR.

This work was supported by the NIH grants DA010355 (J.Q.W.) and MH061469 (J.Q.W.). We thank Dr. Xiaoqiang Yu, Dr. Nilofer Qureshi, and Brian Vukusic for technical support and comments, and Dr. Yves Auberson for providing NVP-AAM077.

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